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1. The sphingosine 1‐phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus.

Author

Magalhães, Daniela M., Stewart, Nicolas A., Mampay, Myrthe, Rolle, Sara O., Hall, Chloe M., Moeendarbary, Emad, Flint, Melanie S., Sebastião, Ana M., Valente, Cláudia A., Dymond, Marcus K., and Sheridan, Graham K.

Subjects
GLATIRAMER acetate, FINGOLIMOD, MONOUNSATURATED fatty acids, HIPPOCAMPUS (Brain), UNSATURATED fatty acids, ION channels, CENTRAL nervous system, MEMBRANE lipids
Abstract

The small‐molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1‐phosphate (S1P) analogue currently used to treat relapsing–remitting multiple sclerosis in both adults and children. FTY720 can cross the blood–brain barrier (BBB) and, over time, accumulate in lipid‐rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor‐mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry‐based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy‐phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up‐regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down‐regulated. FTY720 also modulated anxiety‐like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Mitochondrial dysfunction in Parkinson's disease

Author

Anindita Bose and M. Flint Beal

Subjects
0301 basic medicine, Mitochondrial DNA, Parkinson's disease, PINK1, Substantia nigra, Gene mutation, Mitochondrion, Biology, Biochemistry, DNA, Mitochondrial, Mitochondrial Dynamics, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Animals, Humans, Parkinson Disease, medicine.disease, Cell biology, Mitochondria, Oxidative Stress, 030104 developmental biology, mitochondrial fusion, Mutation, DNAJA3, 030217 neurology & neurosurgery
Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD. Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD. This article is part of a special issue on Parkinson disease.

Published
2016

48. Combination therapy with Coenzyme Q10and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s Diseases

Author

Noel Y. Calingasan, Karen M. Smith, Robert J. Ferrante, Lichuan Yang, Elizabeth Wille, M. Flint Beal, and Kerry Cormier

Subjects
Male, medicine.medical_specialty, Parkinson's disease, Tyrosine 3-Monooxygenase, Ubiquinone, Dopamine, Substantia nigra, Biology, Creatine, Biochemistry, Neuroprotection, Article, Mice, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Huntington's disease, Malondialdehyde, Internal medicine, medicine, Animals, Chromatography, High Pressure Liquid, Coenzyme Q10, Analysis of Variance, Glutathione Disulfide, Pars compacta, MPTP, Deoxyguanosine, Parkinson Disease, Nitro Compounds, medicine.disease, Glutathione, Rats, Mice, Inbred C57BL, Disease Models, Animal, Huntington Disease, Neuroprotective Agents, Endocrinology, nervous system, chemistry, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 8-Hydroxy-2'-Deoxyguanosine, Rats, Inbred Lew, alpha-Synuclein, Drug Therapy, Combination, Lipid Peroxidation, Propionates
Abstract

Coenzyme Q(10) (CoQ(10)) and creatine are promising agents for neuroprotection in neurodegenerative diseases via their effects on improving mitochondrial function and cellular bioenergetics and their properties as antioxidants. We examined whether a combination of CoQ(10) with creatine can exert additive neuroprotective effects in a MPTP mouse model of Parkinson's disease, a 3-NP rat model of Huntington's disease (HD) and the R6/2 transgenic mouse model of HD. The combination of the two agents produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase neurons in the substantia nigra pars compacta (SNpc) following chronic subcutaneous administration of MPTP. The combination treatment resulted in significant reduction in lipid peroxidation and pathologic alpha-synuclein accumulation in the SNpc neurons of the MPTP-treated mice. We also observed additive neuroprotective effects in reducing striatal lesion volumes produced by chronic subcutaneous administration of 3-NP to rats. The combination treatment showed significant effects on blocking 3-NP-induced impairment of glutathione homeostasis and reducing lipid peroxidation and DNA oxidative damage in the striatum. Lastly, the combination of CoQ(10) and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 HD mice. These findings suggest that combination therapy using CoQ(10) and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease and HD.

Published
2009

49. Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer’s disease

Author

Magali, Dumont, Elizabeth, Wille, Noel Y, Calingasan, Davide, Tampellini, Charlotte, Williams, Gunnar K, Gouras, Karen, Liby, Michael, Sporn, Carl, Nathan, M, Flint Beal, and Michael T, Lin

Subjects
Genetically modified mouse, medicine.medical_specialty, Pathology, Amyloid, BACE1-AS, Mice, Transgenic, Plaque, Amyloid, Inflammation, Microgliosis, medicine.disease_cause, Biochemistry, Article, Mice, Cellular and Molecular Neuroscience, Alzheimer Disease, Memory, Cricetinae, Internal medicine, medicine, Amyloid precursor protein, Animals, Oleanolic Acid, Memory Disorders, biology, business.industry, medicine.disease, Triterpenes, Disease Models, Animal, Endocrinology, biology.protein, Female, Alzheimer's disease, medicine.symptom, business, Oxidative stress
Abstract

Oxidative stress is one of the earliest events in the pathogenesis of Alzheimer's disease (AD) and can markedly exacerbate amyloid pathology. Modulation of antioxidant and anti-inflammatory pathways represents an important approach for AD therapy. Synthetic triterpenoids have been found to facilitate antioxidant response and reduce inflammation in several models. We investigated the effect of the triterpenoid, 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic acid-MethylAmide (CDDO-MA) in Tg19959 mice, which carry the human amyloid precursor protein with two mutations. These mice develop memory impairments and amyloid plaques as early as 2-3 months of age. CDDO-MA was provided with chow (800 mg/kg) from 1 to 4 months of age. CDDO-MA significantly improved spatial memory retention and reduced plaque burden, Abeta42 levels, microgliosis, and oxidative stress in Tg19959 mice.

Published
2009

50. Nε-(γ-l-Glutamyl)-l-lysine (GGEL) is increased in cerebrospinal fluid of patients with Huntington's disease

Author

Arthur J.L. Cooper, John E. Folk, John P. Blass, Wayne R. Matson, Marc Yudkoff, Susan E. Browne, Mikhail B. Bogdanov, Lawrence Steinman, Thomas M. Jeitner, Yevgeny Daikhin, and M. Flint Beal

Subjects
chemistry.chemical_classification, Pathology, medicine.medical_specialty, Tissue transglutaminase, Lysine, Biology, medicine.disease, Biochemistry, Molecular biology, In vitro, Cellular and Molecular Neuroscience, Enzyme, Cerebrospinal fluid, chemistry, Huntington's disease, In vivo, medicine, Huntingtin Protein, biology.protein
Abstract

Pathological-length polyglutamine (Q(n)) expansions, such as those that occur in the huntingtin protein (htt) in Huntington's disease (HD), are excellent substrates for tissue transglutaminase in vitro, and transglutaminase activity is increased in post-mortem HD brain. However, direct evidence for the participation of tissue transglutaminase (or other transglutaminases) in HD patients in vivo is scarce. We now report that levels of N(epsilon)-(gamma-L-glutamyl)-L-lysine (GGEL)--a 'marker' isodipeptide produced by the transglutaminase reaction--are elevated in the CSF of HD patients (708 +/- 41 pmol/mL, SEM, n = 36) vs. control CSF (228 +/- 36, n = 27); p < 0.0001. These data support the hypothesis that transglutaminase activity is increased in HD brain in vivo.

Published
2008

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